What is Hypophosphatasia (HPP)?

What is Hypophosphatasia (HPP)?

Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder caused by mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP), resulting in defective bone mineralization, characteristically low serum alkaline phosphatase activity, and a wide spectrum of clinical manifestations ranging from lethal perinatal disease to mild adult-onset symptoms. 1, 2

Pathophysiology

• HPP results from loss-of-function mutations in the ALPL gene (not PHEX gene, which causes X-linked hypophosphatemia—a different condition), leading to deficient TNSALP enzyme activity 1, 3
• The enzyme deficiency causes accumulation of three key substrates: inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP), and phosphoethanolamine 2, 4
• Elevated extracellular PPi blocks hydroxyapatite crystal growth, inhibiting bone mineralization and causing accumulation of unmineralized bone matrix (osteoid) 3
• PLP accumulation can trigger pyridoxine-dependent seizures, particularly in severe infantile forms 2, 4

Epidemiology and Genetics

• Incidence is approximately 1 in 100,000 live births with variable prevalence estimates 2
• Inheritance patterns include both autosomal recessive (severe forms) and autosomal dominant with incomplete penetrance (milder forms) 5, 6
• The disease shows complete penetrance but highly variable expressivity, even within families 2

Clinical Classification and Presentation

HPP is classified into six subtypes based on age of onset 2, 4:

Perinatal/Infantile-Onset HPP

• Most severe form with high mortality risk if untreated 5
• Presents with severe skeletal hypomineralization, respiratory insufficiency due to chest deformity and pulmonary hypoplasia 1, 2
• Characteristic features include rachitic bone changes, fractures, and failure to thrive 1

Juvenile-Onset HPP

• Manifests after 6 months of age with rickets-like bone deformities, premature loss of primary teeth, short stature, and delayed motor development 1, 2
• Bone pain, muscle weakness, and waddling gait are common 2

Adult-Onset HPP

• Clinical manifestations include recurrent metatarsal stress fractures, pseudofractures, osteomalacia, early-onset osteoarthritis, chronic bone pain, muscle weakness, and premature loss of secondary teeth 1, 6
• Chondrocalcinosis, enthesopathies (calcification at tendon/ligament insertions), and nephrocalcinosis may occur 2, 6
• Many adults have history of childhood dental problems or skeletal issues 6

Odontohypophosphatasia

• Isolated dental manifestations with premature tooth loss without skeletal involvement 4

Diagnostic Approach

The hallmark laboratory finding is persistently low serum alkaline phosphatase activity below the age-adjusted reference range 1, 4:

• Elevated serum pyridoxal 5'-phosphate (PLP) and urinary phosphoethanolamine are sensitive and specific biomarkers for HPP 4
• Serum calcium and phosphate levels are typically normal or slightly elevated 2
• Genetic testing with ALPL gene sequencing confirms the diagnosis and should be pursued whenever possible 1, 5

Radiographic Features

• Rickets-like changes in children with metaphyseal irregularities and fraying 2
• Osteopenia, pseudofractures (Looser zones), and premature craniosynostosis may be present 1, 2
• Adults show osteomalacia, stress fractures, and chondrocalcinosis 6

Treatment

Enzyme Replacement Therapy

Asfotase alfa is the only disease-specific treatment approved for HPP, representing a fully humanized recombinant TNSALP enzyme replacement therapy 3, 5:

• FDA-approved for perinatal/infantile-onset and juvenile-onset HPP at a dose of 2 mg/kg administered subcutaneously three times weekly (6 mg/kg/week total) 3
• Mechanism: Replaces deficient TNSALP enzyme, reducing substrate accumulation (PPi and PLP) and improving bone mineralization 3, 5
• Clinical benefits include improved skeletal mineralization, respiratory function, muscle strength, growth velocity, and survival in severe pediatric forms 5, 7
• In adults, treatment results in subjective improvement in muscle strength (up to 70%), walking ability (up to 100% increase in distance), bone pain reduction, and enhanced quality of life 7
• Most common adverse effect is injection site reactions; the drug is generally well-tolerated 7
• Pharmacokinetics show steady-state achievement within 3 weeks, with elimination half-life of approximately 5 days 3

Important Treatment Considerations

• Clinical improvement typically becomes noticeable after 3 months of therapy 7
• The higher concentration formulation (80 mg/0.8 mL) achieves approximately 25% lower systemic exposure compared to lower concentration formulations at the same dose 3
• Anti-drug antibody formation can reduce systemic exposure and treatment efficacy 3

Supportive Care

• Prior to asfotase alfa availability, treatment was purely palliative with high morbidity and mortality 2
• Orthopedic interventions for fractures and deformities may be necessary 1
• Dental care is critical given high risk of tooth loss and abscesses 1
• Physical therapy for muscle weakness and mobility issues 7

Off-Label Therapies in Adults

• Teriparatide and anti-sclerostin antibodies have been used off-label in selected adult cases to accelerate fracture healing and treat concomitant osteoporosis 2

Key Distinctions from X-Linked Hypophosphatemia (XLH)

HPP must be distinguished from X-linked hypophosphatemia (XLH), which is caused by PHEX gene mutations and characterized by elevated (not low) alkaline phosphatase, hypophosphatemia with renal phosphate wasting, and elevated FGF23 levels 1:

• XLH shows low serum phosphate with renal phosphate wasting, whereas HPP typically has normal phosphate levels 1
• XLH has elevated or inappropriately normal FGF23 levels, while HPP does not involve FGF23 dysregulation 1
• Alkaline phosphatase is elevated or normal in XLH but characteristically low in HPP 1, 4

Clinical Pitfalls to Avoid

• Do not dismiss low alkaline phosphatase as a laboratory error—it is the diagnostic hallmark of HPP and warrants further investigation 4, 6
• Avoid attributing symptoms solely to osteoporosis or arthritis in adults without checking alkaline phosphatase levels 6
• Early diagnosis and treatment initiation are critical as delayed treatment is associated with worse outcomes and irreversible complications 1, 5
• Multidisciplinary care coordinated by a metabolic bone disease specialist is essential given the systemic nature of the disease 1